Novel Insights from Clinical Practice

Ocul Oncol Pathol 2018;4:381–387

Scleral Thinning after Transscleral Biopsy for Uveal Melanoma Using Lamellar Scleral Flap

Diane T. Siegel

a Eszter Szalai

a Jill R. Wells

a Hans E. Grossniklaus

a, b a

Department of Ophthalmology, Emory University School of Medicine, Atlanta, GA, USA; b

Department of Pathology, Emory University School of Medicine, Atlanta, GA, USA

Received: September 4, 2017Accepted after revision: January 17, 2018Published online: February 23, 2018

Hans E. Grossniklaus, MD1365B Clifton Road, NESuite BT428Atlanta, GA 30322 (USA)E-Mail ophtheg @ emory.edu

© 2018 S. Karger AG, Basel

E-Mail karger@karger.comwww.karger.com/oop

Established Facts

• The transscleral biopsy technique for uveal melanoma without the use of a lamellar scleral flap is as-sociated with a low risk of complications.

• Distinguishing scleral necrosis from extraocular tumor extension can be difficult and is made on the basis of clinical findings.

Novel Insights

• The use of a partial-thickness lamellar scleral flap may increase risk of development of scleral thinning and possible extraocular tumor extension.

• A scleral flap for biopsy of uveal melanoma should be used with caution.

DOI: 10.1159/000487007

KeywordsUveal melanoma · Transscleral biopsy · Lamellar scleral flap · Scleral necrosis · Scleral thinning

AbstractPurpose: The purpose of the study is to describe the clinical history and histopathologic findings of three cases of scleral thinning after lamellar scleral flap, including one case with confirmed extraocular tumor extension. Methods: The med-ical records and pathology specimens of three patients with scleral thinning after biopsy and plaque brachytherapy and lamellar scleral flap performed during a transscleral biopsy

were reviewed. Results: The first two patients developed scleral thinning and visible pigmentation, but had tumors that were regressing in size on ultrasound. The two patients were followed by serial observation. The third patient exhib-ited scleral thinning and evidence of tumor growth on ultra-sound, raising the suspicion for extraocular tumor extension. Histopathologic examination of the enucleated eye con-firmed extrascleral tumor extension and showed necrotic and intact melanoma with associated pigmented macro-phages. Conclusions: Patients with scleral flaps created for biopsy of uveal melanoma are at risk for scleral thinning and extrascleral extension of tumor recurrence through the flap.

© 2018 S. Karger AG, Basel

Siegel/Szalai/Wells/GrossniklausOcul Oncol Pathol 2018;4:381–387382DOI: 10.1159/000487007

Introduction

Uveal melanoma is a neoplasm of melanocytes located within the choroid, ciliary body, or iris and is the most common primary intraocular malignant neoplasm in adults [1]. Diagnosis is typically based on findings from the clinical exam and additional imaging tests, such as ultrasound and fluorescein angiography [2]. However, fine-needle aspiration biopsy (FNAB) is now commonly performed to obtain tissue sample for cytogenetic testing and gene expression profiling, which can help assess risk for metastasis [3, 4]. Treatment of uveal melanoma usu-ally consists of plaque brachytherapy and enucleation [5].

We have recently evaluated three eyes with uveal mel-anoma which had FNAB using a lamellar scleral flap at the time of plaque brachytherapy placement and subse-quently developed scleral thinning over the flap site. Two eyes then developed melanocytic proliferation over the site of the scleral flap and one resulted in extrascleral tu-mor extension, requiring enucleation.

Case Reports

Case 1A 75-year-old woman presented to our clinic to establish care

and follow-up for choroidal melanoma in the left eye. She was di-agnosed 4 years prior and received iodine-125 episcleral plaque brachytherapy at another institution. The total radiation dose in-formation was not available. At that time, a transscleral FNAB was performed, using a 57 blade to create a partial thickness scleral flap and a 27-gauge needle to aspirate tumor material. The scleral flap was closed with 9–0 nylon sutures. Gene expression profiling re-vealed class 2 melanoma.

At presentation, her best corrected visual acuity was 20/40. Slit-lamp examination showed scleral thinning over flap site with cho-roid showing, vitreous hemorrhage, trace pigment cells in the vit-reous, and a brown mass in the anterior periphery. An ultrasound was performed, which showed an elevated choroidal lesion in a dome-shaped configuration, measuring 4.5 mm in thickness and 10.3 × 9 mm in basal diameter. These measurements represented a decrease in size from prior measurements. Repeat slit-lamp ex-amination 7 months later showed increased scleral thinning and ultrasound remeasurement revealed a regressing tumor, 3.8 × 9.9 × 8.9 mm in size (Fig. 1, Fig. 2). Because the tumor had decreased in size, this was felt to represent scleral thinning and melting of the scleral flap secondary to radiation therapy. The patient is being fol-lowed by serial observation.

Case 2A 55-year-old male was referred to our clinic for management

of choroidal melanoma in the right eye. Four months previously, a choroidal lesion was noted incidentally on a routine MRI of the brain for his multiple sclerosis. Ultrasound revealed a tumor mea-

suring 8.8 × 10.8 × 11.9 mm with a mushroom-like configuration. The A-scan component showed low internal reflectivity. About 1 month later, the patient underwent iodine-125 plaque brachyther-apy, receiving a total dose of 85 Gy to 8.8 mm, and a transscleral FNAB. The surgeon used a 15-degree blade to make a partial thick-ness scleral flap and a 25-gauge needle to aspirate a specimen. The flap was closed using 8–0 nylon sutures. The tumor was found to be a class 1A subtype on gene expression profiling.

At a follow-up visit 20 months after presentation, VA was 20/100, which pinholed to 20/40, and slit-lamp examination was notable for scleral thinning and a pigmented lesion. The tumor had decreased in size to 3.1 × 9.0 × 10.6 mm by ultrasound examination (Fig. 3, Fig. 4). The pigmentation again was thought not to repre-sent extraocular extension, but rather scleral thinning with an un-derlying treated melanoma. The patient is being followed by serial observation.

Case 3An 80-year-old woman was evaluated in our clinic for ongoing

management of a choroidal melanoma in the left eye. Her tumor had been treated 6 years previously with iodine-125 plaque brachy-therapy, receiving a total of 84 Gy to 13.5 mm. At the time of plaque placement, she underwent a transscleral FNAB using a 15-degree blade to create a partial thickness scleral flap and a 25-gauge needle to aspirate tumor material. Gene expression profiling showed a class 1A tumor. Since then, her visual acuity decreased to light per-ception and she had no pain.

At the time of evaluation, slit-lamp examination was notable for a brown mass protruding at an area of scleral thinning tempo-rally, peripheral neovascularization of the cornea, a shallow ante-rior chamber filled with cholesterol, vascularization of the iris, and no view of posterior ocular structures (Fig. 5).

Ultrasound showed extrascleral extension of the tumor through the area of scleral thinning (Fig. 6). The tumor measured 14.5 mm in thickness (including the anterior protrusion) with a base mea-suring 16.4 × 15.0 mm. These measurements represented an in-crease in size from prior measurements.

Given concern for extraocular extension of melanoma, the eye was enucleated. Gross examination of the enucleated eye revealed a heavily pigmented choroidal mass nasally with an overlying scleral defect and the mass extended through the sclera onto the epibulbar surface (Fig. 7). The tumor had broken through Bruch’s membrane and assumed a mushroom-shaped configuration. His-topathologic examination showed that approximately 70% of the tumor was necrotic, with the surrounding portion composed of heavily pigmented cells. The tumor cells were plump, polyhedral cells with centrally placed, small, bland nuclei, and abundant cy-toplasm, which was engorged with pink melanin pigment gran-ules. There were scattered melanophages and cholesterol clefts within the tumor. The tumor extended through the sclera, onto the episclera surface, where it formed a nodule, which was covered by a thin layer of fibrovascular tissue. Some tumor cells in the scleral surface had spindle-shaped or oval nuclei with centrally placed nucleoli and marginated chromatin. Examination of the soft tissue adjacent to the optic nerve and the superonasal and in-ferotemporal vortex veins showed no signs of malignancy. The final diagnosis was malignant melanoma, mixed cell type arising in melanocytoma, and extensive necrosis and extraocular exten-sion.

Scleral Flaps for Uveal Melanoma 383Ocul Oncol Pathol 2018;4:381–387DOI: 10.1159/000487007

a b

a b

a b

Fig. 1. Case 1. a Appearance of sclera at time of presentation. b One month later, the biopsy site shows a larger, darker protrusion.

Fig. 2. Case 1. a B-scan ultrasound at the time of presentation shows an anteriorly located mass measuring 4.5 × 10.3 × 9.0 mm. b Seven months later, the tumor measures 3.8 × 9.9 × 8.9 mm.

Fig. 3. Case 2. a Fourteen months after initial presentation, scleral thinning and a dark mass are evident. b Six months later, the areas of scleral thinning and dark mass are larger.

Siegel/Szalai/Wells/GrossniklausOcul Oncol Pathol 2018;4:381–387384DOI: 10.1159/000487007

Discussion

All three of our cases developed scleral thinning after transscleral FNAB using a partial thickness scleral flap and radiation treatment of their tumors. Although other etiologies of scleral thinning, such as inflammation from tumor necrosis or surgically induced necrotizing scleri-tis, are possible, we believe that these cases demonstrate scleral necrosis secondary to radiation therapy. There have been several reports in the literature of scleral ne-crosis after plaque brachytherapy [6–11]. Overall, how-ever, it is a relatively rare occurrence (1%) and the aver-age time to development of scleral necrosis after radia-tion therapy is 32 months [12]. The cases that we describe here developed of scleral thinning within a comparable

timeframe. Our case 1 developed scleral thinning within 31 months after treatment, case 2 within 19 months, and case 3 within 29 months, all consistent with the prior re-port.

Risk factors of scleral necrosis include: increasing tu-mor thickness (> 6 mm), ciliary body and peripheral cho-roidal location (pars plana to ora serrata location of the anterior tumor margin), and higher radiation dose to the sclera (> 400 Gy to the outer sclera) [12]. Before plaque placement, case 1 was 6 mm thick, case 2 was 8.8 mm thick, and case 3 had a tumor thickness of 13.5 mm. All three of our cases had anteriorly located tumors.

The diagnosis of scleral necrosis is based on clinical findings and must be distinguished from extrascleral tu-mor extension to avoid unnecessary enucleations or risk

a b

Fig. 4. Case 2. a B-scan ultrasound from the initial presentation shows an anteriorly located tumor measuring 8.8 mm in thickness with a base that measured 10.8 × 11.9 mm. b B-scan ultrasound from a follow-up visit 20 months after presentation shows that the tumor measured 5.0 × 8.9 × 11.6 mm.

a b

Fig. 5. Case 3. a Appearance of the scleral thinning approximately 3 years prior to b, which shows the mass to have enlarged with more protrusion through the sclera.

Scleral Flaps for Uveal Melanoma 385Ocul Oncol Pathol 2018;4:381–387DOI: 10.1159/000487007

of metastasis. In 1999, Corrêa et al. [9] described a case of early-onset scleral necrosis with tumor extrusion within 1 month of plaque radiotherapy in a 62-year-old with a large ciliochoroidal melanoma, which was treated with enucleation. The distinction between scleral necrosis and tumor extension can be difficult. For example, Hill and

Corrêa [13] describe a case of scleral necrosis in an eye treated with brachytherapy for uveal melanoma that sim-ulated extension of the tumor, though no tumor cells were found outside the sclera once the eye was enucleat-ed. Furthermore, Kaliki et al. [12] found no evidence of scleral involvement of melanoma in 8 eyes that were enu-

a b

a b

Fig. 6. Case 3. B-scan ultrasound images (a, b) show that the residual tumor had increased in size from prior imaging, and exhibits ex-trascleral extension (asterisks).

Fig. 7. Case 3. a The enucleated eye contains a pigmented mass protruding through breaks in the sclera (arrows). b There are intact melanoma cells extending through the sclera (hematoxylin and eosin, 100×).

Siegel/Szalai/Wells/GrossniklausOcul Oncol Pathol 2018;4:381–387386DOI: 10.1159/000487007

cleated for suspected tumor extensions and signs of scler-al necrosis. Ultrasound biomicroscopy (UBM) or anteri-or segment optical coherence tomography (AS-OCT) can be useful in distinguishing between scleral necrosis and extrascleral tumor extension [12]. UBM and AS-OCT im-ages in our cases were not available.

Scleral necrosis alone can be managed conservatively with observation and lubrication with artificial tears, gels, or ointments [12]. Other management options for scleral necrosis include scleral patch graft, conjunctival graft/flap, amniotic membrane transplantation, and enucle-ation, depending on the severity and concern for possible perforation [12, 14]. We elected to closely observe case 1 and case 2 because they showed only scleral thinning and melanomacrophage proliferation thus far but no increase in tumor size.

Our case 3 showed evidence of scleral thinning and increased subconjunctival pigmentation 3 years prior to enucleation. Later, ultrasound measurements that in-cluded the anterior protrusion of the tumor showed an increase in thickness, raising suspicion for likely extra-scleral tumor extension, which was confirmed once the eye was enucleated. Recurrence of melanoma after radia-tion therapy is rare, with a recurrence rate of 3–4.2% after several years of follow-up [15, 16]. Local recurrence is as-sociated with a greater risk of distant metastasis, which some hypothesize to be related to the greater malignant potential of the primary uveal melanoma [15].

FNAB of uveal melanomas is generally accepted to be a safe procedure with a low risk of complications [3, 4, 17, 18]. However, there are a few rare case reports in the lit-erature of extrascleral tumor extension after FNAB [19–21]. None of the FNAB techniques referenced in the case reports definitively describe the use of a partial thickness scleral flap in a transscleral FNAB at the time of plaque brachytherapy placement.

To our knowledge, there has been no discussion in the literature of the role that a lamellar scleral flap may play in the development of future scleral necrosis or extra-scleral tumor extension. In one prospective case series, Singh et al. [18] described outcomes in 150 eyes which had FNAB of uveal melanoma, including 71 eyes which had a partial thickness scleral flap at the time of their transscleral biopsy and plaque placement. They reported no tumor recurrence, but did not comment on develop-ment of scleral necrosis in the average of 37 months of follow-up [18]. Another recent study on complications of FNAB in uveal melanoma did not appear to include a la-mellar scleral flap in their transscleral FNAB technique [17].

The primary techniques used for FNAB include a transvitreal approach for posteriorly located tumors and transscleral methods for anterior lesions. The use of a la-mellar scleral flap in the transscleral technique was ini-tially popularized due to concerns for seeding of tumor cells in the subconjunctival space using a straight needle approach. Angi et al. [22] describe a biopsy technique for anteriorly located tumors that consists of an incisional biopsy using Essen forceps through a lamellar scleral flap later sealed by histoacryl glue; this technique improved specimen yield for cytological and genetic analysis com-pared to the traditional transscleral FNAB technique. This technique includes a near full thickness flap with a wide flap that allows for spreading of the tissue glue. They did not report any tumor recurrence, and did not report on the presence of scleral thinning over their me-dian follow-up time of 9.8 months [22]. We made trian-gular flaps that measured approximately 3–4 mm at the base by 3–4 mm to the apex, 0.5 mm thick, and closed the flaps with one or two 8–0 nylon sutures at or near the apex; we did not use histoacryl glue. These differences from the Angi technique may have predisposed for scler-al thinning.

Our cases illustrate a possible risk of scleral necrosis and possible extrascleral tumor extension in patients who have had plaque brachytherapy and partial thickness scleral flap during FNAB. It is possible that a variation on the lamellar scleral flap biopsy technique, as described by Angi et al. [22], may avoid the complications of scleral necrosis and extrascleral tumor extension. However, fur-ther study is needed. Given the potential to confuse the clinical picture, our recommendation is to take precau-tions when using a lamellar scleral flap during transscleral biopsy.

Acknowledgements

We would like to thank Drs. Christopher Bergstrom and Prith-vi Mruthyunjaya for their participation in the care of these patients and Elizabeth Butker for providing information about the radia-tion doses of the plaques.

Statement of Ethics

The study followed the tenets of the Declaration of Helsinki. The Emory University Institutional Review Board granted exempt status to this study.

Scleral Flaps for Uveal Melanoma 387Ocul Oncol Pathol 2018;4:381–387DOI: 10.1159/000487007

Disclosure Statement

The authors declare no conflicts of interest.

Funding Sources

Supported in part by NIH P30EY06360 and an unrestricted departmental grant from Research to Prevent Blindness, Inc.

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